This program is dedicated to the translation of basic research findings into clinical trials of novel therapies for inflammatory bowel diseases (IBD) AND to using basic research methods to define the immune and genetic mechanisms underlying IBD in a variety of settings. This year's research accomplishments include: 1. Publishing results of a multi-center Phase II study of an anti-IL-12 antibody for active Crohn's disease (NEJM 351:2069-79,2004). Anti-IL-12 treatment caused significant improvement in symptoms vs placebo (3mg/kg sc q week for 7 weeks) and induced remissions in many patients. Beneficial responses were accompanied by significant decreases in Th1 inflammatory cytokines (measured in subjects enrolled at the NIH). These results are particularly relevant because they established the effectiveness of targeting IL-12 in Crohn's disease, showed that IL-12 is an important inflammatory cytokine driving disease even in chronic stages, and they demonstrate the advantage of targeting therapies at proximal points in an inflammatory cascade. 2. Reporting new findings that another Th1 cytokine, IL-23, plays a role in the inflammation of Crohn's disease (Gastroenterology128:A-118,2005). This is important because it presents the possibility that other Th1 cytokines may play a significant role in ongoing inflammation and that therapies targeting IL-23 specifically (e.g. the p19 subunit) should be tested for safety and effectiveness in Th1 diseases like Crohn's. 3. Reporting new findings that the often-devastating intestinal inflammation that can complicate Common Variable Immunodeficiency (Gastroenterology 128:A505,2005) is a Th1-mediated process that appears different from Crohn?s disease in its lack of a role for IL-23. This finding is important because there is no treatment for this form of IBD (it does not respond to the chronic replacement of immunoglobulin that controls the frequent infections) and I am currently putting in place a new treatment protocol for these patients based on anti-IL-12 strategies. 4. Publishing results of the NIH experience with gastrointestinal disease in Hermansky-Pudlak syndrome (Clin. Gastroenterol. Hepatol.,2005 in press). Hermansky-Pudlak syndrome (HPS) is a model inherited disease for study of IBD etiology because it is caused by a defect in interacting proteins due to single gene mutations on different chromosomes. Patients with HPS have loss of pigment in the skin and eye (oculocutaneous albinism) with reduced vision, a platelet disorder leading to easy bleeding, and may develop pulmonary fibrosis. Patients with HPS also have a risk of IBD over ten-fold greater than the general population; the colitis may be granulomatous and we show that it is associated with only two of the known HPS gene defects. These findings are important because they summarize such data on the largest group of HPS subjects so studied, and the data suggest a genetic animal model to test susceptibility to IBD and measure individual function of the various parts of the mucosal immune system (from colonic biodiversity to molecular and cellular aspects of the innate and adaptive mucosal immune system) that may be affected by these defects. Current active NIH protocols included in this program (Dr. Mannon as PI): 82-I-0183 Studies of the Immune Regulation of Idiopathic Inflammatory Bowel Diseases: Crohn?s Disease, Ulcerative Colitis, and Undefined Inflammatory Conditions of the Gut 02-I-0153 The Immune Basis for the Gastrointestinal Complications of Common Variable Immunodeficiency 02-I-0019 Granulocyte-Colony Stimulating Factor Treatment for Crohn?s Disease: A Pilot Study Assessing Immune and Clinical Response 03-I-0019 An Open-label, Pilot Study of Type I Interferon Treatment of Ulcerative Colitis 03-I-0177 A Single Arm Study of Extracorporeal Photoimmune Therapy with UVADEX for Corticosteroid Sparing in Patients with Corticosteroid-dependent Crohn's Disease Refractory or Intolerant to Immunosuppressants and/or Anti-TNF Agent 04-I-0231 Procurement of Clinical Specimens for Immunologic or Genetic Studies in Inflammatory Bowel Diseases 05-I-0108 A Multicenter, Open-label, Study of Extracorporeal Photoimmune Therapy with UVADEX in the Treatment of Patients with Moderately Active Crohn's Disease Who Are Refractory or Intolerant to Immunosuppressants and/or Anti-TNF Agent